The proposed research will characterize the effects of nicotine and cigarette smoking on regional cerebral blood flow (rCBF). The goals are to identify brain regions involved in the reinforcement processes that underlie tobacco dependence. Two studies will be conducted with cigarette smokers to identify rCBF effects of nicotine and to measure changes in these effects after subjects receive a pharmacologic treatment that blocks smoking reward. In Study 1, eighteen smokers will receive nicotine-containing smoke, de-nicotinized smoke that contains negligible nicotine but which provides significant tar and sensory' aspects of smoking, or sham smoke, which contains neither tar nor nicotine. rCBF will be measured before and after each condition using O15 positron emission tomography (PET). Doses of nicotine will be individualized to match subjects' preferred level of self-administered nicotine during ad lib smoking. The de-nicotinized cigarette smoke will be used to control for the non-nicotine constituents of tobacco smoke and to assess the influence of conditioned reinforcement on rCBF. In Study 2, rCBF effects of nicotine and cigarette smoke will be assessed before and after subjects receive a pharmacologic treatment which previously has been shown to attenuate craving and facilitate abstinence from cigarettes. This treatment entails administration of the nicotinic antagonist mecamylamine in combination with the nicotine skin patch. Changes in rCBF will be correlated with treatment outcome. The results of these studies will help guide future research toward brain regions likely to be involved in nicotine craving and reward, and should ultimately improve our understanding and treatment of tobacco dependence.